MECHANISM OF PESTICIDE MIREX INDUCED TUMOR PROMOTION

描述：灭蚁灵是一种氯化农药， 原型皮肤肿瘤启动子：i）通过未鉴定的 与其他皮肤肿瘤促进剂不同的机制; ii）似乎促进 表皮或表皮附属细胞的独特群体， 然而，与佛波醇酯促进的那些不同， 不能通过其突变的Ha-ras基因型区分; iii）是4-5倍 在雌性小鼠中更有效;和iv）克隆扩增突变体群体 Ha-ras细胞似乎依赖于雌激素。 局部雌激素 治疗本身对毛囊周期有深远的影响， 阻断休止期卵泡向生长期卵泡的转变， 可能是通过其直接作用或通过其对皮肤的调节， 或影响增殖的真皮乳头衍生因子，和/或 推定隆突干细胞的分化/瞬时扩增（TA） cell. FGF家族成员是已知的毛发的有效调节剂 毛囊以及表皮的生长和分化。 我们假设 雌激素直接或间接通过FGF家族影响 推定的干细胞/TA细胞的分化导致表型 这对灭蚁灵的推销很敏感。 本提案的具体目标 是; i）最终证明雌激素和雌激素 灭蚁灵促进作用的受体依赖性; ii） 皮肤中的雌激素受体和循环毛囊，并确定 雌激素调节FGF成员及其受体的表达; iii） 确定灭蚁灵引起的乳头状瘤的皮肤起源和表型 关于雌激素受体和FGF，它们的同源受体， iv）证明灭蚁灵与 雌激素/雌激素调节的FGF在角质形成细胞中的作用。 对此进一步研究 一种新的肿瘤促进剂将使人们对灭蚁灵， 环境氯代农药，与雌激素的界面作用 在皮肤中作为一种有效的肿瘤促进剂。 拟议的研究还将 有助于我们了解雌激素和FGF在 调节毛囊的生长、发育和分化; 上皮/间质相互作用;以及影响 推定的表皮干细胞/TA细胞向肿瘤的分化 启动子特异性表型。 对灭蚁灵作用机理的认识 晋升将是重要的，在确定其他成员， 类，并最终对非遗传毒性的合理风险评估 致癌物质。

DESCRIPTION: Mirex is a chlorinated pesticide and represents a potent prototypical skin tumor promoter that: i) functions through an unidentified mechanism distinct from other skin tumor promoters; ii) appears to promote a unique population of epidermal or epidermal appendage cells that are different than those promoted by phorbol ester, however, this population cannot be distinguished by its mutant Ha-ras genotype; iii) is 4-5 times more potent in female mice; and iv) clonally expands a population of mutant Ha-ras cells that appears to be dependent upon estrogen. Topical estrogen treatment itself has a profound effect on the hair follicle cycle by blocking the transition of the telogen follicle to an anagen follicle, presumably through its direct effect or through its modulation of dermally- or dermal papilla-derived factors that influence proliferations and/or differentiation of the putative bulge stem cell/transient amplifying (TA) cell. Members of the FGF family are known potent modulators of hair follicle as well as epidermal growth and differentiation. We hypothesize that estrogen directly or indirectly through the FGF family influences the differentiation of the putative stem cell/TA cell resulting in a phenotype that is sensitive to mirex promotion. The specific aims of this proposal are to; i) conclusively demonstrate the estrogen- and estrogen receptor-dependent nature of mirex promotion; ii) localize the expression of the estrogen receptor in skin and the cycling hair follicle and determine if estrogen modulates the expression of FGF members and their receptors; iii) identify the cutaneous origin and phenotype of the mirex promoted papillomas with respect of the estrogen receptor, and FGFs, their cognate receptors and iv) demonstrate a functional interaction between mirex and estrogen/estrogen-modulated FGF in keratinocytes. Further study of this novel tumor promoter will yield a fundamental understanding of how mirex, an environmental chlorinated pesticide, interfaces with estrogen, to function as a potent tumor promoter in skin. The proposed studies will also contribute to our understanding of the role of estrogen and FGF in the regulation hair follicle growth, development and differentiation; epithelial/mesenchymal interactions; and factors that influence the differentiation of putative epidermal stem cells/TA cells to a tumor promoter specific phenotype. An understanding of the mechanism of mirex promotion will be important in the identification of other members of this class and ultimately to the rational risk assessment of nongenotoxic carcinogens.